The long-term objective of the proposed research is to significantly improve the management of thyroid nodules through non-invasive detection and classification of cancer using high-frequency quantitative ultrasound (QUS). According to one study, the number of suspect thyroid nodules detected in clinical evaluations is up to 70% of the adult population. It is estimated that more than 300,000 fine needle aspiration (FNA) biopsies of the thyroid will be conducted this year in the United States alone. FNA performed on thyroid nodules requires the time and services of the point-of-care physician, the time and services of a pathologist, and time, discomfort, and anxiety of the patient. However, a vast majority of thyroid nodules undergoing FNA turn out to be benign. The development of high-frequency QUS imaging will almost certainly decrease the stress, discomfort, and anxiety of the patient and could markedly reduce the burden of pathologists by reducing the necessity of many FNA procedures. Furthermore, if a novel imaging system could be developed that was quantitative and operator independent, the utility of the device would improve care in facilities where expertise is not as profound due to smaller patient loads. For most thyroid nodules, conventional ultrasonic imaging is unable to give a definitive diagnosis. We hypothesize that high-frequency QUS will allow the diagnosis of thyroid cancer non-invasively and significantly improve management of thyroid nodules by providing up to six independent quantitative parameters related to the tissue microstructure. To test the hypotheses that high-frequency QUS can improve the management of thyroid nodules, two specific aims are proposed. The first specific aim is to develop models of tissue scattering and QUS from normal thyroid, benign thyroid lesions, and malignant thyroid lesions using a three-dimensional impedance map (3DZM) approach. Optical photomicrographs and resulting 3DZMs will be used to construct new models for tissue scattering from thyroid cancer in the animal models and to identify structures that will be described by QUS estimates. By comparing predicted ultrasonic signals using the 3DZMs with actual measured signals from the same tissue, the source of scattering can be identified. Furthermore, the role of the microstructural organization to scattering and the subsequent ultrasonic signal will be determined through 3DZMs. The second specific aim is to demonstrate the ability of QUS imaging techniques to classify nodules for benign, cancerous, and type of cancer in vivo from animal models of thyroid cancer. Normal thyroid, benign thyroid nodules, and cancerous thyroid lesions in mice will be examined and QUS techniques applied to determine the capability to classify the lesions in vivo. Diagnosis will be confirmed via optical photomicrographs of the tumors and independent pathology reports. The optical photomicrographs will then be incorporated into the first specific aim as an iterative technique for identifying scattering sources and construction of more sensitive QUS models. PUBLIC HEALTH RELEVANCE: Up to 70% of the adult population has detectable thyroid nodules creating a crisis in the proper management of these nodules. High-frequency quantitative ultrasound can provide up to six independent parameters related to the tissue microstructure of thyroid nodules. The increased diagnostic information provided by high-frequency quantitative ultrasound will drastically improve the management crisis of thyroid nodules.